Genetic counseling: Duchenne Muscular Dystrophy-1
Duchenne Muscular Dystrophy Contracting *Discuss the reason for referral **Express sympathy for the recent loss of son and brother **Who is the referring physician? *Obtain written consent to use son/brother's records for session and for testing **From mother **Tell me about your son/brother *Elicit prior knowledge about MD carrier testing **CK testing ever done? = creatine phosphokinase **Did anyone else ever address carrier status with them? **What is the perceived risk of being a carrier? *Assess concerns **What will she do with the information? **Discuss pros and cons of knowing carrier status ***Reproductive decisions, planning for the future, prenatal diagnosis options ***Stress, anxiety, fear *Set goals for the session *Provide overview of topics for counseling session **Review personal and family history **Discuss inheritance pattern **Risk of being a carrier **Testing process and delivery of results **Decide if you would like testing today ***Emphasize that it is VOLUNTARY Intake & Family History *Pedigree **Any other affected family members? *Psychosocial assessment **Who have you told about the appointment? **Who will you tell about the results? **Do you have a serious boyfriend? **How would the results affect your future reproductive plans? **What was it like growing up with a brother who had DMD? General Information *Dystrophinopathies **Characterized by a spectrum of muscle disease that ranges from mild to severe **Duchenne/Becker muscular dystrophy is severe ***Skeletal muscle is primarily affected in both ***DMD is rapidly progressive and presents in early childhood. ****Patients are often wheelchair-bound by age 12 ***Becker is characterized by later-onset skeletal muscle weakness ****Patients remain ambulatory into their 20s *Dystrophin gene **Xp21.2 **Encodes protein dystrophin **Often deletions or duplications involving exons of this gene **Molecular genetic testing is available clinically *Prevalence **1 in 5,600 live male births **1/3 of patients are new mutations and the mother is not a carrier Diagnosis *Clinical **Family history ***Compatible with X-linked recessive inheritance **Creatine Phosphokinase (CK) concentration ***Evaluated by blood test ***Elevated serum CK concentration results from progressive elimination of dystrophic muscle fibers. ****Can also result from strenuous exercise ***CK concentration gradually decreases with advancing age due to the progressive elimination of these muscle fibers. ***100% of males with DMD have a serum CK concentration >10x normal ***~50% of female carriers have a concentration 2-10x normal ****Some investigations have shown a wide variability in DMD carriers ****Many have levels within the normal range, so other tests are necessary ****CPK is not completely reliable **Muscle biopsy ***Histology ****Shows non-specific dystrophic changes ***Western blot and immunohistochemistry ****Dystrophin protein is often completely or almost completely absent **Clinical findings ***Progressive symmetrical muscle weakness, proximal greater then distal ***Symptoms before age 5 years ***Wheelchair dependency before age 13 years *Molecular genetic testing **Deletions involving one or more exons of the DMD gene ***~65% of males with DMD have deletions ***Most deletions occur in two hotspots clustered around the first 20 exons and around exons 45 to 55. ***Testing is done by PCR or southern blot ***Available on a clinical basis **Duplications of one or more exons of the DMD gene ***~6% of males with DMD have a duplication ***Testing is done by southern blot or quantitative PCR ***Available on a clinical basis **Other mutations in the DMD gene ***~30% of males with DMD have other mutations including small deletions or insertions, single base changes, or splicing mutations ***Analysis is available on a research basis only **Carrier testing may be performed but requires quantitative analysis for gene dosage which can be difficult to perform and interpret **Prenatal testing is available Clinical Description *Males **DMD usually presents in early childhood with delayed milestones ***This included delays in sitting and standing ***First symptoms are typically: ****General motor delay ****Gait problems including persistent toe-walking and flat-footedness ****Delay in walking *****Mean age of walking is about 18 months ****Learning difficulties ****Speech problems **Mean age of diagnosis without a family history is about 4 years ***Range of diagnosis is 16 months to 8 years **DMD is rapidly progressive ***Proximal weakness causes a waddling gait and difficulty climbing ***Boys use the Gower maneuver to rise from a supine position, using the arms to supplement weak pelvic girdle muscles ***The calf muscles are hypertrophic and firm to palpation ***Occasionally there is calf pain ***Affected children are wheelchair-bound by age 12 ***Mean age of death is 17 or 18 years of age **Cardiomyopathy ***Incidence increases steadily in the teenage years ****1/3 of patients are affected by age 14 ****½ by age 18 ****All patients are affected after age 18 ***Few affected males survive beyond the third decade ****Respiratory complications and cardiomyopathy are common causes of death **Cognitive impairment ***Some degree of nonprogressive impairment is common ***Affects the verbal ability more than nonverbal performance **Phenotype correlates with the degree of expression of dystrophin ***Expression is largely determine by the reading frame of the spliced message *Females **Occasionally have DMD clinical features as the result of X chromosome rearrangements involving the DMD locus (Xp21.2) **Carriers can have DMD because of Turner syndrome of nonrandom X chromosome inactivation **76% of DMD carriers have no signs or symptoms *Management **There is no treatment for DMD ***Prednisone therapy is controversial due to side effects ****Some report improvement in strength and function which begins within 10 days and plateaus after 3 months ****Long term benefit has not been demonstrated **Appropriate management can prolong survival and improve quality of life ***Physical therapy to promote mobility ****Range-of-motion exercises ***Braces to delay the onset of contractures ***Monitoring and surgical intervention for orthopedic complications ****Scoliosis, kyphosis, or lordosis ***Routine monitoring for evidence of cardiomyopathy **All carriers should have a complete cardiac evaluation at least once Differential Diagnosis *Limb-girdle muscular dystrophy **A group of disorders clinically similar to DMD **Occurs in both sexes **Caused by mutations I genes that encode sarcoglycans and other proteins that interact with dystrophin *Emery-Dreifuss muscular dystrophy **Associated with limb contractures and cardiac arrhythmia **X-linked recessive, autosomal dominant, and autosomal recessive forms **Caused by mutations in the LMNA gene *Spinal muscular atrophy **Caused by mutations in the SMN gene **Characterized by: ***Poor muscle tone ***Symmetric muscle weakness that spares the face and ocular muscles ***Evidence of anterior horn cell involvement ****Includes fasciculations of the tongue and absence of deep tendon reflexes *Dilated cardiomyopathy **Can be sporadic or familial *No other phenotypes are associated with mutations in the DMD gene Inheritance *X-linked recessive **Carrier females have a 50% chance of transmitting the DMD mutation in each pregnancy **With each pregnancy, a carrier has a 25% chance of having an affected child *Risk to family members **A woman with an affected son and one other affected relative in the maternal line is an obligate heterozygote **A woman with more than one affected son and no other family history can have: ***A germline mutation ****DMD disease-causing mutation present in every cell ***Germline mosaicism ****Mosaicism for a DMD disease-causing mutation which includes the germline ****The frequency of germline mosaicism in DMD is estimated at 12% to 20% **If proband is only affected family member, must determine if mother and other females are carriers ***The proband may have a de novo DMD disease-causing mutation ****The mutation could have occurred in the egg at the time of conception ****The mutation could have occurred after conception and therefore is present in some but not all cells of the proband's body. ****The likelihood that the mother is a carrier is low ***The proband's mother may have a de novo mutation ****2/3 of mothers of sporadically occurring males with DMD are carriers ****Could have occurred if: *****Mutation occurred in the egg or sperm at the time of her conception and is present in every cell of her body (germline mutation) *****Mutation is present in some but not all cells of her body (somatic mosaicism) *****Mutation is present only in her egg cells (germline mosaicism) and is not detected in a blood sample. ***The proband's mother may have inherited a DMD mutation from her mother who is a carrier, her mother or father who has somatic mosaicism, or her mother or father who has germline mosaicism. Risk Assessment *Sporadic versus inherited **If inherited, sister has 50% chance of being a carrier **Bayes analysis takes into account 3 unaffected male siblings ***Sister has a 1/18 or 5.5% chance of being a carrier **1/3 of cases are due to sporadic mutation Review and summarize major points Elicit final questions and concerns Ordering the test *Patient must sign consent form for DNA analysis **Use blue ink so it is obvious which is the original **Give the patient a copy **Put the original in the chart *Use special specimen processing request form **Make a copy for the chart **Give a copy to Lori Martineek at E352 *Blood is drawn at Test Referral Center **Pt must have consent form, 2-ply specimen processing request form, and DNA analysis requisition **Tell pt to make sure her name is on the tube of blood **TRC will FedEx to Dr. Prior's lab *Contact Dr. Thomas W. Prior to inform him that you are sending the sample **Prior-1@medctr.osu.edu **Give him clinical history and lab report # from prior testing Arrange for Follow-up *How do you want to receive the test results? **Results may take 2-3 weeks **We will only be able to give the results to the person tested, not to mother *Give potential risk figures if positive and emphasize that she can come back for more information at any time **Some people may wait for years until they are thinking of starting a family *Send a clinic letter after the results are back Resources *Muscular Dystrophy Association **800-572-1717 **www.mdausa.org *Gale Encyclopedia of Medicine **Muscular Dystrophy by Richard Robinson (1999) **From the CHMC Health Reference Center References *About Muscular Dystrophy. A booklet sponsored by the Muscular Dystrophy Association. 1981. *www.mdausa.org (Muscular Dystrophy Association) *www.geneclinics.org (GeneClinics) *Emery and Rimoin's Principles and Practice of Medical Genetics. Third Edition, 1996. pp 2337-2354 *Nelson's Textbook of Pediatrics. 15th Edition. pp1745-1748 *Online Mendelian Inheritance in Man (OMIM). DMD#310200, Dystrophin#300377 Notes The information in this outline was last updated in 2002. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.